PONE-D-20-02954

Unveiling Prognostics Biomarkers of Tyrosine Metabolism Reprogramming in Liver Cancer by Cross-platform Gene Expression Analyses

PLOS ONE

Dear Dr. Nguyen TN,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, I feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Although the reviewers found the study interesting, they raised a number of serious points that do not allow me to accept the manuscript on the basis of how it is currently presented. Therefore, I invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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2. We noticed minor instances of text overlap with the following previous publication(s), which need to be addressed:

(1) https://www.hindawi.com/journals/omcl/2018/7512159/

The text that needs to be addressed involves the second paragraph of the Introduction section.

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

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5. Review Comments to the Author

Reviewer #1: Thank you very much for inviting me to review the manuscript- “Unveiling Prognostics Biomarkers of Tyrosine Metabolism Reprogramming in Liver Cancer by Cross-platform Gene Expression Analyses” by Nguyen et al.

The authors evaluate the role of tyrosine metabolism in liver cancer development. They explore multiple public gene expression datasets and find that five Tyrosine catabolic enzymes are down regulated in HCC and also that they have prognostic significance.

The authors should include more details in the first three paragraphs of the results section like p values, number of samples, correlation ratios.

The TGCA data set has 50 normal tissues. The authors say that they use 160 normal tissues. Did they also include normal tissue from GTEX.

Did the stage of HCC in the TCGA cohort correlate with levels of the 5 enzymes.

It is not clear why the author chose to further explore GSTZ1 and not the other enzymes. The prognostic value of GSTZ1is not convincing based on the tcga data.

The authors show the pathway analysis of GSTZ1 overexpression in huh7 cells. They do not explain what the phenotype of overexpression was. Was it increased proliferation or decreased apoptosis?

The discussion section needs to be made more succinct and relevant to the current manuscript.

Figure 3 shows prognostic relevance of the five catabolic enzymes in the Tyrosine pathway. Four of the genes are divided by median and 182 patients are in the high and 182 pts in the low category. But GSTZ1 shows 73 patients in the high and 91 patients in the low. Can the author's explain why this is?

In figure 4 authors should include more representative samples from the public pathology database. They currently show just one core for each. Number of samples should be included in the y-axis

In Figure 6 authors show survival curves for mir539 and mir661. The number of patients in the denominator appear different for both of them. For mir539 the high category has 225 patients. For mir661 there are 82 patients in the high category.

I would skip this sentence “We further discovered that the expression of GSTZ1, the fourth rate limiting enzyme in tyrosine catabolism, regulates glycolytic gene expression”. Their analysis is exploratory and cannot be considered a true discovery.

Authors conclude by saying that they report a “novel function for tyrosine catabolic genes in tumorigenesis”. Other papers have alluded to a role for tyrosine metabolism in cancer. I would avoid using broad claims for novelty and focus on specific findings of this paper.

Unveiling Prognostics Biomarkers of Tyrosine Metabolism Reprogramming in Liver Cancer by Cross-platform Gene Expression Analyses

PONE-D-20-02954R1

Dear Dr. Nguyen,

I carefully checked your comments and addictions to your paper and I am pleased to inform you that your manuscript has been now judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Francesca Megiorni, Ph.D.

Academic Editor

PLOS ONE